CD27 belongs to the TNF-Receptor (TNFR) family, members of which regulate the propensity of a cell to grow or die. The ligand for CD27 is CD70, which belongs to the TNF family of ligands. Extensive work done by several groups have shown that CD27/CD70 interaction provides costimulatory signals for T cell growth and enhances B cell differentiation and Ig synthesis. Regulated expression of CD27 in mature thymocytes implies a role for it in thymic differentiation. A soluble form of the receptor (sCD27) has been detected in the serum of normal individuals and its levels were found to be elevated in patients with autoimmune disorders and certain B cell cancers. During our attempts to understand mechanisms underlying CD27 signaling, unexpectedly, we found that ligation of CD27 by CD70 transfectants resulted in apoptosis in the B cell lines Raji and Ramos. Since CD27 is clearly involved in costimulation and cell signaling with carefully regulated expression in vivo, we believe that CD27 induced apoptosis plays a major role in the clearance of activated T or B cell clones. The elevated sCD27 observed in patients with autoimmune disorders and B cell cancers may well contribute to the pathologic process by interfering with CD27 induced apoptosis. The cytoplasmic tails of TNFR1 and Fas (but not CD27) have the 'death domain' which is indispensable for induction of apoptosis through these receptors. How then is CD27 able to induce apoptosis? and does it occur in cells where Fas is ineffective? In order to understand the molecular mechanisms underlying this novel apoptotic pathway, using CD27 cytoplasmic tail as the bait in the yeast two hybrid system, we cloned a novel CD27 cytoplasmic tail binding protein Siva-1 which when expressed in various mammalian cells can induce apoptosis. Accordingly, we propose that Siva-1 mediates the apoptotic effects of CD27. Structural features of Siva-1 include a death domain homology region (DDHR), box-B like ring finger and a Zn finger like domain. We also identified an alternate splice form of Siva-1 (Siva-2) which lacks most of the DDHR and does not induce apoptosis, supporting our proposal that the DDHR of Siva-1 is the downstream conduit of the proapoptotic function of CD27. We propose to fully define the roles of Siva-1 and -2 in CD27 induced apoptosis, map the functional domains of Siva-1 and Siva-2 and determine whether Siva-1 and Siva-2 work in concert to regulate the apoptotic function of CD27. These studies should provide important insights into the regulatory role of cell surface molecules in T and B cell function.